Pandemic influenza is one of the largest infectious disease threats to the human population. These pandemics occur when novel influenza A viruses enter the human population having the potential to cause catastrophic disease. This potential is highlighted by the 1918 Spanish influenza pandemic that swept the globe on its way to infecting 25-40% of the world's population and killing millions of people. Influenza pandemics again emerged in 1957 and in 1968, each killing an estimated 1 million people during their first waves.
Influenza A virus subtype H5N1, also known as A(H5N1) or simply H5N1, is a subtype of the Influenza A virus which can cause illness in humans and many other animal species. A bird-adapted strain of H5N1, called HPAI A(H5N1) for “highly pathogenic avian influenza virus of type A of subtype H5N1”, is the causative agent of H5N1 flu, commonly known as “avian influenza” or “bird flu”. It is endemic in many bird populations, especially in Southeast Asia.
While there is not yet efficient human-to-human transmission or airborne transmission of H5N1 to humans, the virus does have a high mortality rate when humans are infected, and Influenza A is capable mutation and reassortment, which could lead to a more effectively transmitted disease. Certain events have taken place that could increase the possibility of a pandemic, including the spread of disease to new areas through migratory birds.
Another set of issues is that phylogenic and genetic analyses of the H5N1 viruses circulating in Asia have identified three main clades of contemporary virus, see Chen et al. (2005) Nature 436:191-192. The viruses isolated in Vietnam, Thailand, Malaysia, Cambodia, and Laos belong to one group (clade II), the viruses from Indonesia (and some from China) represent another (clade III), and the viruses from migratory birds in China (and probably Russia) make up the third (clade I). Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections. Antigenically, the isolates from groups I and II are distinct. Unfortunately, antigenic information concerning the group III viruses is limited, but phylogeny of the HA gene suggests that it too will be distinct from viruses of the other groups. Because it cannot be predicted from which H5N1 group the pandemic virus may emerge, it is necessary that any vaccination or antiviral strategy have the capacity to inhibit viruses from each. A critical question of the current vaccines in clinical studies is their ability to induce cross-clade neutralizing antibodies. Antibodies against H5N1 are discussed by Simmons et al. (2007) PLOS 4:e178.
The extreme virulence of this virus and its growing geographic distribution urge the development of targeted therapeutic and prophylactic measures. Already H5N1 vaccines have entered clinical trials worldwide and they offer the best means of mass protection. However, it is likely the first line of defense against an emerging pandemic will need other options including antivirals. In addition, for certain patients such as the elderly, infants, and immunocompromised hosts, a limited response to vaccination will require other preventive measures.
Currently, the two options for treating influenza are the M2 ion channel blockers (e.g., amantadine) and the neuraminidase inhibitors (e.g., oseltamivir and zanamivir). Unfortunately, many of the current H5N1 viruses are resistant to amantadine and a higher dose and longer treatment schedule of oseltamivir is needed for protection in murine models, proof that other options are very much needed.
An alternative prevention measure is to develop antibody-based therapeutics to neutralize viruses representing each of the three clades, or cross-clades. Preventing disease with specific high-titer antibody preparations has been established for a wide-range of infectious agents including hepatitis A virus, hepatitis B virus, herpesviruses (VZV and CMV), rabies, and measles. The value of specific antibodies in treating infectious disease has been also demonstrated for transplant recipients with CMV infection (in combination with ganciclovir), parvovirus B19 in immunocompromised patients, and RSV infection in premature infants to name a few examples. These antibody preparations are mostly derived from human polyclonal sera although in recent years humanized monoclonal antibodies have been developed.
Due to the high lethality and virulence of H5N1, its endemic presence, its increasingly large host reservoir, and its significant ongoing mutations, the H5N1 virus presents a serious pandemic threat. Agents that can be used in the prevention or treatment of this disease are of great interest.